Evaluating the Options in Correcting Dyslipidemia

Lipid-Lowering Trials

The first study of lipid-lowering agents that included a substantial diabetic cohort was the Helsinki Heart Study, which randomized 4,081 healthy middle-aged men without evidence of coronary heart disease (CHD) or type 2 diabetes, and who had non-HDL-C levels of 200 mg/dL or more, to either placebo, or gemfibrozil.[5] A total of 135 patients with diabetes were included. After 5 years of follow-up, the diabetic cohort had more than twice as many cardiac events (MI or cardiac death), with an incidence of 7.4%, compared with 3.3% in the nondiabetic population (P < .02).

Overall, the gemfibrozil-treated group had a 34% reduction in cardiac events attributable to the medication. In the diabetic cohort, there was a 60% reduction in event rate for patients with diabetes on gemfibrozil compared with placebo. The group randomized to gemfibrozil showed an incidence of 3.4%, compared with 10.5% in the placebo group (P = .19), a difference that was not, however, statistically significant due to the small number of patients with diabetes in the cohort and the low event rate.[5] Thus, there was a trend toward more frequent cardiovascular events in patients with diabetes than in nondiabetics with comparable hypercholesterolemia. There was also a marked decrease in the rate of cardiovascular events due to lipid-lowering therapy with gemfibrozil.

Some critics of the study have suggested that the significant reduction in cardiac events was due mostly to an LDL reduction in the gemfibrozil-treated group and not to the rise in HDL and decrease in triglycerides that gemfibrozil produces. Nonetheless, the diabetic participants appeared to receive a greater benefit from gemfibrozil therapy than did nondiabetics, even though the patients with diabetes experienced a lesser degree of reduction in their total cholesterol, triglycerides, and LDL, and smaller increases in HDL than did nondiabetics on drug therapy. Thus, triglyceride-lowering therapy appears to have a beneficial effect in patients with type 2 diabetes.

In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial(VA HIT), patients with low levels of HDL as their predominant lipid abnormality were treated with gemfibrozil; patients with diabetes were included in the trial, but there was no stratification for diabetes in the report.[6] In this trial, gemfibrozil-treated patients showed a substantial (31%) reduction in plasma triglycerides, a modest (6%) increase in HDL-C, and a slight increase in LDL-C levels of 4%. In spite of this rise in LDL-C, there was a 22% reduction in the combined end points of MI and cardiac death compared with the placebo-treated patients. Thus, pharmacologic treatment of patients with high triglycerides and low HDL-C will produce cardiovascular benefits.

The Scandinavian Simvastatin Survival Study (4S) demonstrated improved survival among diabetic and nondiabetic patients with CHD and hypercholesterolemia after treatment with a statin.[7] A total of 4444 patients with documented heart disease (angina or previous MI) and elevated total cholesterol, with triglycerides no greater than 2.5 mmol/L and total cholesterol between 5.5 and 8.0 mmol/L, were randomized in equal numbers to simvastatin or placebo.

After a median follow-up of 5.4 years, the simvastatin group had mean changes in total cholesterol (-25%), LDL (-30%), HDL (+8%), and triglycerides (-10%). Coronary deaths were less frequent in the simvastatin-treated group: There were 189 in the placebo group and 111 in the simvastatin group, representing a 42% re-duction in CHD mortality attributed to simvastatin. Deaths from other causes were comparable in the two groups.

The 202 patients with diabetes in the 4S study were analyzed separately by Pyorala and colleagues.[8] Of the 202 diabetic participants, 97 were randomized to placebo and 105 to simvastatin. Compared with the nondiabetics, the diabetic group had slightly higher initial triglyceride levels and lower HDL-C levels but comparable total cholesterol and LDL-C levels.

Reductions in total cholesterol, triglycerides, and LDL-C, and increases in HDL-C levels were comparable for the simvastatin-treated patients with diabetes and the simvastatin-treated nondiabetics. At the end of the 5-year study, simvastatin-treated nondiabetics showed a 32% reduction in the risk of MI or cardiac death. A full 55% reduction in MI or cardiac death was demonstrated among the patients with diabetes treated with simvastatin. As many as 45% of patients with diabetes treated with placebo had one of these events, compared with 23% of the patients with diabetes who received simvastatin. Patients with diabetes who received placebo had substantially higher rates of coronary events that were apparent as early as 2 years into the study. Thus, the study showed that treating hypercholesterolemia in patients with diabetes will improve their survival.

Unlike the 4S trial, which tested the effect of lowering cholesterol in patients with severe hypercholesterolemia, the Cholesterol and Recurrent Events (CARE) trial[9] enrolled patients who had a previous MI but only "average" rather than elevated levels of cholesterol in order to determine whether lipid lowering would result in significant secondary prevention. A total of 4159 patients, with total cholesterol less than 240 mg/dL (mean, 209 mg/dL) and LDL-C less than 175 mg/dL (mean, 139 mg/dL) were randomized in equal numbers to treatment with pravastatin or placebo for 5 years. Baseline lipids in both groups were essentially identical, with serum triglycerides of 155 mg/dL and HDL of 39 mg/dL. After 5 years, patients receiving pravastatin were found to have a 24% reduction in the risk of a significant cardiovascular event (fatal CHD or confirmed MI), demonstrating that reducing LDL levels from average (mean, 139 mg/dL) to low (mean, 97 mg/dL) decreases recurrent cardiac events.[9]

A subset analysis of the patients with diabetes in the CARE trial was subsequently performed.[10] The baseline lipid levels of these 586 patients with diabetes were similar to those of the overall CARE patients enrolled, with slightly higher triglycerides (164 mg/dL in the diabetic cohort versus 156 mg/dL overall), but the patients with diabetes tended to be older, more obese, and more hypertensive. While patients with diabetes and nondiabetics showed reductions in LDL-C levels, patients with diabetes who received pravastatin showed a greater reduction in the risk of recurrent cardiac events than nondiabetics who received pravastatin (25% versus 23%, respectively). Likewise, the patients with diabetes receiving placebo had higher recurrent event rates than the nondiabetics receiving placebo (37% versus 25%).

Among the 3553 CARE patients who identified themselves as nondiabetic, 342 were found by the fasting glucose test at study entry to have impaired fasting glucose (IFG), defined as a fasting glucose level of 110 mg/dL to 125 mg/dL. These 342 patients with IFG represented a substantial proportion -- 8% -- of the population of patients enrolled, all of whom had prior MI.

A statistically significant increase in the relative risk of MI or death from CHD occurred in patients with a fasting glucose level greater than 110 mg/dL, compared with patients with a fasting glucose level at or below that level. Compared with patients with fasting glucose levels less than 110 mg/dL, those with IFG (110 mg/dL to 126 mg/dL) were older (60 years for IFG versus 58 years for those with fasting glucose levels less than 110 mg/dL), heavier (BMI 29 versus BMI 27), with larger waist circumference (99 cm versus 94 cm), higher triglycerides (170 mg/dL versus 151 mg/dL), lower HDL (37 mg/dL versus 39 mg/dL), and higher systolic blood pressure (131 mm Hg compared with 128 mm Hg). All of these differences were statistically significant.[9] Thus, the cohort with IFG had all the features of insulin resistance, even before they developed hyperglycemia. Patients with IFG who received pravastatin had a decreased risk of cardiac events compared with placebo-treated patients with IFG, although the difference was not statistically significant due to the small number of IFG patients in subset analysis. Early insulin resistance, identified by the surrogate marker of elevated fasting plasma glucose, appears to confer a dramatically increased risk of cardiovascular events.

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References

Authors and Disclosures

Authors and Disclosures

Dr. Reasner is associate professor of medicine and chief of clinical endocrinology at the University of Texas Health Sciences Center and Medical Director, Texas Diabetes Institute, University Center for Community Health, San Antonio.

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